Discussion

Veldhuis: You have tackled an interesting problem that few groups have studied, partly because of the complex confounding by concurrent drugs. Dr Greet Van den Berghe has managed to find a fairly homogeneous population that has convinced many ofus that there is excellent pituitary responsiveness to a host of releasing factors, particularly given in combination (Van den Berghe et al 1997a,b, 1998,1999a,b, 2000,2001a,b).

Bowers: One of the surprises of the GHRP2 is that as one gives it continuously, it would be expected to down-regulate the effect. But it is only partially down-regulated because there is a persistent increase of pulsatile secretion. We have done this study in older individuals up to 30 days, and in one individual for 90 days. The increased pulsatile secretion of GH remains sustained. When we give acute bolus injections of GHRP2, the GH response is markedly desensitized. However, during chronic infusion pulsatile GH secretion is augmented. In the elderly studies there was a difference between males and females. In some of the men, GHRP2 did not work very well, so we gave it in combination with GHRH. My interpretation of these data is that the women do not have as much endogenous GHRH deficiency. GHRP2 is ineffective unless one has endogenous GHRH. I assume that these women have more GHRH reserve. Men have more ofa deficiency of both the natural GHRP hormone, ghrelin, and GHRH.

Laron: I have had discussions with several of our colleagues about the fact that to achieve the anabolic effects of GH, pulsatile secretion is not necessary. What is the benefit of using secretagogues rather than IGF1 or GH?

Bowers: That is not a simple question. When one gives GH itself, there is a sustained level and there will be more side effects. By stimulating pulsatile secretion one can get the same effects as with GH. This means that there is much less GH secreted and indicates how efficacious the effects of pulsatile GH are on peripheral targets. Comparatively, when one administers GH the levels are high. Another issue is the difficulty of determining the dose of GH that should be given if GH is to be given exogenously. By the GHRP approach, GH levels are totally determined by the feedback system. On each patient the effect is individualized internally by the patient's feedback response.

Laron: You are saying that by using this technique, one would be able to reduce the very high sensitivity to GH in the aged population, while we still don't know the lowest (minimal) effective dose.

Bowers: With regard to the total quantity of GH needed, one can obtain the same effect with a small quantity of pulsatile GH secretion as with administration of GH at larger doses.

Veldhuis: The IGF feedback on the GHRP2 system is so effective that if one happens to overdrive GH output and IGF comes up, it will restrain the GH

(Giustina & Veldhuis 1998). I was under the impression that GH levels rise promptly under continued infusions, and as the IGF1 levels rise the GH levels fall about 50%. The system re-sets at a higher level of IGF.

Müller: I was impressed by the findings shown by Dr Shalet that the pulsatile secretion of GH changes so dramatically from the acute phase to the chronic phase, in spite of similar serum concentrations of peripheral IGF1.

Carroll: I want to raise a philosophical question. We are used to thinking of stress responses as adaptive. There is a long tradition of this viewpoint for acute stress responses. We never evolved to survive in intensive care units: there was no opportunity for selection on this success! Are we to look at these hypothalamic changes as adaptive stress responses, or as allostatic changes? Are we to look on them, therefore, as pathological and in need of treatment?

Shalet: I think these are unnatural changes, because this is a very abnormal set of circumstances.

Bowers: But there is an under-stress response in that second phase, it is not a full stress response. Since these patients are still under stress during the second phase, the full capacity of normal stress responses appears to be impaired and the stress response is inappropriately low.

Carroll: It is some kind of adaptive response, but whether it will promote survival is another matter.

Shalet: It is a failing system.

Carroll: You moved very quickly over the cortisol data. There are very good data, for example, from burns units, showing sustained elevation of cortisol going on for weeks, and a severe drop in production of cortisol binding globulin. How much of the other axis changes are attributable to a primary change in cortisol?

Shalet: That is a plausible suggestion. You could argue the case in terms of changes in gonadotrophin or GH secretion. There are a number of possible hypotheses to explain the endocrine findings in protracted critical illness, and this would be one. We hardly touched at all on the use of other drugs in these patients. In critical care, even if we exclude dopaminergic drugs, we haven't mentioned opiates.

Handelsman: We have done a study similar to this. We don't see testosterone levels of as low as 1 nM in men unless there is something more even than this huge stress response. For example, hypercortisolism alone does not seem to produce that. What does is opiates. Burns patients in particular, are on opiates for long periods of time. I don't know the data that you present very well, but I suspect that there is an opiate effect there that we should take into account.

Shalet: In fairness, in some of the studies Dr Van den Berghe has tried to look at statistical differences in terms of opiate use or not. This is presumably a fairly crude overview of opiate use.

Handelsman: With regard to the aromatase, I don't doubt the observations, but the interpretation of whether a change in the oestradiol:testosterone ratio in peripheral blood indicates a change in aromatase is suspect. Only 0.2% of the body's production of testosterone is converted to oestradiol on a whole body basis. Just this very fact alone should necessitate caution. In addition, clearance rate differences in oestradiol will give all sorts of changes, especially in this setting. I would be hesitant to take this interpretation further.

Shalet: Dr Van den Berghe raises the issue ofthe increased fat mass that occurs in protracted critical illness. This may well contribute to the 37-fold increase in aromatase activity. Changes in catecholamines and TNFa levels may also be contributory factors.

Elahi: I have been discussing some work with respect to hypoglycaemia that persists during this time. The therapy is glucose, potassium and insulin. There are other modes of therapy currently under investigation, which are less risky. Would the therapies you mention exaggerate the glucose excursion?

Shalet: I don't think Dr Van den Berghe's data touch on this. I would say that she has moved on, and another key hormone she is focusing on at the moment is insulin. This will be a key measure in her future studies.

Ruiz-Torres: I am interested in the relationship between the hormonal changes in critical illness and those which appear during ageing. I have some doubts regarding the value of this model for studies on ageing. For instance, each critical illness has high dysproteinaemia as a common manifestation. The consequence is a decrease of plasma protein transport and an increase of the distribution volume. For this reason, the blood levels of hormones, substances, or drugs are decreased. What happens afterwards is dependent not only on feedback mechanisms but also on a wide range of other factors produced by toxins and intermediary products.

Shalet: Let me answer you simply. I hope I portrayed in my presentation that I didn't see this as a marvellous model for ageing. I tried to be careful there. But there were some similarities in the behaviour of certain axes. Even if what you said is true (and I'm sure that much of it is), you still have to explain things like the gender variation in GH secretion which is very striking.

Veldhuis: A 30% drop in blood volume puts an adult into shock. If you are talking about any hormone changes of several-fold, you don't have to worry that distribution volume is the sole explanation: it won't be for changes of that magnitude.

Prior: In a study of women post-premenopausal ovariectomy, their initial fasting HDL levels were —1.5 standard deviations compared to the normal age range. These were not women with cardiovascular risk factors and their HDL levels subsequently came into the normal range over the next three months. When I looked at this I found that there are reports in the literature of low HDL

in association with acute trauma or illness. What do people think the mechanisms might be?

Veldhuis: This is a protein that is under negative control by insulin, like others such as IGFBP1. Beyond this, and the high insulin output that occurs during hyperalimentation regimens, it is not clear to me what would lower HDL in these women. The half-life is presumably several weeks.

Prior: These women were not on hyperalimentation: they were just fasting post-operatively.

Laron: Stephen Shalet, considering the Scandinavian data you have presented in both acute phase and in chronic illness, what is your advice concerning GH therapy?

Shalet: The simple answer is that I don't know. The dose of GH used in the intensive care study was something like 20 units per day, whereas a standard GH replacement dose is of the order of 1.2 units daily. This was a very big dose of GH. Considering what we have heard, I am attracted to the approach that Dr Van den Berghe and her colleagues are following, which is to begin to look at combinations of pituitary hormone secretagogues. I can't say more about the insulin side. I know Dr Van den Berghe feels that insulin is going to be a key factor in terms of outcome. Do I personally see a big place in this discussion for GH? 'Not particularly' would be my immediate reaction. Other strategies look more attractive to me. The one area where I think the data are most promising for GH therapeutically would be the burns patients. The data look reasonable but are limited.

Giustina: You mentioned that the combination of GHRP2 and TRH may be effective in modifying some target organ effects. You explain this by implying that GHRP has an effect on the GH axis, and TRH has an effect on the thyroid axis. If I remember correctly, in critical illness, as occurs in other situations such as acromegaly and type 1 diabetes, TRH may have some GH-stimulating action. Might this be a combination acting mainly via the GH axis?

Shalet: Individual pituitary hormone secretagogues contribute significantly to the effect on other pituitary hormone axes when used in combination.

Bowers: Van den Berghe found that TRH by itself had very little effect; it was only when she put it together with GHRP2 that she got an additional effect.

Carroll: In terms of intervention, in the near future we will have CRH antagonists for human use. These have already been looked at in animal models of delirium tremens, alcohol withdrawal and drug withdrawal. Drugs like CRH antagonists will probably show great promise for managing the centrally driven hyperstimulated hypothalamic—pituitary—adrenal states. Critical illness might well be a clinical context where they will find application.

Bjorntorp: I have a vague memory of having heard about studies in which GH has been used to treat heart failure. What is the current situation?

Shalet: The first paper, as I recollect, was by Fazio et al (1996). There were seven patients with dilated cardiomyopathy, and the results were encouraging in terms of improvement in cardiac function. To my knowledge, at least two subsequent controlled studies from Sweden (Isgaard et al 1998) and Germany (Osterziel et al 1998) did not show benefit.

Giustina: The issue is very complex. The selection of patients is probably critical in understanding the results of giving GH to patients with heart failure. There are probably some patients with a certain degree of GH resistance. These are the patients who are not likely to benefit from standard doses of GH.

Elahi: I presume you were talking about the paper by Fazio et al (1996). We were very stimulated by this study. So far we have looked at four patients with congestive heart failure. We gave them 21 d of GHRH therapy. Their IGF1 levels rose following therapy. We administered GHRH 1 mg qd and a month later, 2 mg qd. We now have switched to *2 mg/day given in four equal pulses, every 2 h from 23:00 to 05:00 h. The total dose of 30 mg/kg is split into four pulses. Whereas with a 1 mg dose, nothing happened, with 2 mg we saw a substantial increase in IGF1 levels. Having said this, it is only one-third of the response seen in normal age-matched low-IGF volunteers. We are doing positron emission tomography (PET) scans to see whether we get any changes in protein synthesis in the heart.

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